Human CD1comprise a family of antigen presentation molecules with a unique tissue distribution that includes skin. Experiments performed in our laboratory indicate that CD1-restricted T cells recognize lipid antigens and can contribute to cell-mediated immunity in leprosy. Here, we propose to explore the immunobiology of antigen presentation by CD1 in human disease, by investigating the cutaneous lesions of leprosy. Our specific aims are as follows: 1) Elucidate the structure of antigens presented by CD1a and explore the mechanism of antigen processing and presentation of CD1a-restricted antigens. This aim is based on our finding that Langerhans cells, dendritic cells resident in the epidermis, present novel nonpeptide antigens to T cells via langerin and CD1a. We propose to identify the structure of the antigen(s) presented by CD1a to T cells and determine the role of langerin in the CD1a antigen presentation pathway in Langerhans cells. 2) Determine the functional role of CD1-restricted T cells in skin by comparing CD1-restricted T cells derived from leprosy skin lesions according to the pattern of secreted cytokines, cytolytic and antimicrobial activity and their ability to provide help for B cells in the production of antibodies. We propose to determine whether the CD1-restricted T cells have specific function according to the CD1 isoform restriction element, given that each CD1 molecule has a distinct cellular distribution pattern. 3) Investigate the mechanism for CD1 downregulation in leprosy skin lesions. Our preliminary data indicate that mycobacteria reduce CD1 expression by activation of the nuclear receptor PPAR-gamma. We propose to determine the mechanism by which mycobacteria activate PPAR-gamma and how activation affects host immune responses. The studies we propose are intended to provide a comprehensive analysis of CD-1 restricted T-cell function in relation to a model of human skin disease, with particular emphasis on their role in immunity.